ACSL1 Is Associated With Fetal Programming of Insulin Sensitivity and Cellular Lipid Content

Mol Endocrinol. 2015 Jun;29(6):909-20. doi: 10.1210/me.2015-1020. Epub 2015 Apr 27.

Abstract

Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Adipogenesis / genetics
  • Animals
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Coenzyme A Ligases / metabolism*
  • Cytokines / metabolism
  • Epigenesis, Genetic
  • Fetal Development*
  • Gene Knockdown Techniques
  • Genetic Association Studies
  • Glucose / metabolism
  • Histones / metabolism
  • Humans
  • Infant, Newborn
  • Infant, Small for Gestational Age
  • Insulin / metabolism*
  • Lipid Metabolism*
  • Lysine / metabolism
  • Mesenchymal Stem Cells / cytology
  • Mice, Obese
  • Oligonucleotide Array Sequence Analysis

Substances

  • Cytokines
  • Histones
  • Insulin
  • ACSL1 protein, mouse
  • Coenzyme A Ligases
  • ACSL1 protein, human
  • Glucose
  • Lysine

Grant support

This work was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore-NMRC/TCR/004-NUS/2008 and NMRC/TCR/012-NUHS/2014. Singapore Institute for Clinical Sciences Investigators are supported through Agency for Science, Technology and Research funding.